Certain somatic fusion genes have been known to be drivers of cancer initiation and progression. Mittelman, F., et al. (2007) Nature Reviews Cancer 7: 233-245. The first, now classic, example of a cancer-promoting fusion gene is the BCR-ABL1 fusion gene that is found in over 95% of chronic myelogenous leukemia (chronic-phase CML) patients. The BCR-ABL1 gene encodes a constitutively active form of ABL kinase. The optimal frontline treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves relatively specific inhibitors of the BCR/ABL tyrosine kinase. Currently marketed inhibitors include first generation drug imatinib (current first line treatment) and second generation drugs nilotinib, dasatinib, bosutinib and ponatinib. Fusion genes were also found to occur with high frequencies in other hematological cancers. Annala, M. J., et al. (2013) Cancer Lett. 340: 192-200. The ETV6-RUNX1 and BCR-ABL1 fusions appear in 25% and 14%, respectively, of acute lymphocytic leukemias, the RUNX1-ETO and CBFB-MYH11 fusions in 10-15% of acute myeloid leukemias, the IG@-MYC fusion in 90-100% of Burkitt's lymphomas, the PML-RARA fusion in 95% of acute promyelocytic leukemias, and the NPM1-ALK and TPM-ALK fusions in 75% and 15%, respectively, of anaplastic large cell lymphomas. While fusion genes historically were detected with relatively high frequencies in hematological cancers, they were only found in a small fraction of solid tumors. More recently, however, it became clear that fusion genes could also occur with elevated frequencies in solid tumors. Annala et al. (2013). Fusions of TMPRSS2 and members of the ETS family of transcription factors were found in about 70% of prostate cancer patients. EML4-ALK fusions can be present in non-small cell lung cancers, KIAA1549-BRAF fusions in pediatric glioma and FGFR3-TACC3 fusions in glioblastoma. Comprehensive listings of known fusion genes are found, e.g., in Annala et al. or in Shaw, A. T. et al. (2013) Nature Reviews Cancer 13: 772-787. It is noted that some fusions can occur in different cancers. As an example, TPM3-ALK fusions were identified in anaplastic large cell lymphoma and in inflammatory myofibroblastic tumors. Other ALK fusions occur in non-small lung cell cancers as well as in anaplastic large cell lymphoma.
Fusions can be cancer-promoting by different mechanisms. In the case of BCR-ABL, for example, the BCR partner provides dimerization domains, causing constitutive dimerization of the ABL domain, which results in constitutive ABL kinase activity and, consequently, uncontrolled cell division. An alternative mechanism is at play in the case of the TMPRSS2-ETS fusions found in prostate cancer. In these fusion genes, a sequence coding for an ETS transcription factor is brought under the control of the androgen-regulated TMPRSS2 promoter, causing the transcription factor to be overexpressed. Overexpressed ETS dysregulates the expression of genes associated with normal prostate epithelial differentiation and causes uncontrolled cell proliferation. In yet another mechanism, up-regulation of the expression of the FGFR polypeptide can result from the loss of a miRNA regulation site in the 3′UTR of the FGFR mRNA, which loss occurs when the FGFR gene fuses with another gene. Parker, B. C. et al. (2013) J. Clin. Invest. 123: 855-865.
Discovery and characterization of fusion genes advance cancer therapy in multiple ways. Taking as examples fusion genes encoding activated tyrosine kinases, e.g., ABL1, ALK, ROS1, RET and FGFR1-3, identification of such fusion genes in cancerous tissue from patients motivates the discovery and development of selective or specific inhibitors directed against the relevant kinases. The presence of fusion kinase genes also informs the choice of therapeutic approach. For example, the first line treatment for chronic-phase CML patients expressing BCR-ABL1 fusion kinase is a regimen comprising BCR-ABL kinase inhibitor imatinib. Discovery of fusion kinase genes provides a basis for devising diagnostic assays that are capable of discovering the presence of such genes or the expression of the products of such genes in tissues from a cancer patient. As discussed for chronic-phase CML, a positive diagnosis of the presence of a fusion kinase gene or of gene products thereof in a tumor tissue of a patient will allow a physician to decide on the most appropriate therapy regimen. Typically, such a regimen will include administration of a composition that inhibits the expression or the activity of the fusion kinase in question.
There is no reason to believe that all fusion genes relevant to cancer (or other diseases) are now known. The discovery and characterization of additional fusion genes is expected to increase the specificity of cancer treatment subsequent to the development of diagnostic methods for the newly discovered fusion genes or polypeptides and the development or identification of specific inhibitors of the newly discovered fusion genes or polypeptides or of other agents directed to the fusion genes or polypeptides. In fact, there is an increasing need for identifying specific subpopulations, for example, among cancer patients who would benefit the most from a given treatment such as a therapy involving a particular kinase inhibitor.